Screening,Characterization And Evaluation Of Supramolecular Complexes Based On Insoluble Drugs

The common solid complexes based on active pharmaceutical ingredients?API?involve salts,cocrystal and co-amorphous.Pharmaceutical cocrystal is a new crystalline form composed of an API and a cocrystal former?CCF?by hydrogen bond or other non-covalent bonds.The co-amorphous phase?CAP?is an amorphous complex formed by the combination of an API and a co-amorphous former?CAF?with hydrogen bonds or other non-covalent bonds.Both cocrystal and CAP can improve the solubility,dissolution rate,bioavailability and other physiochemical properties of API with not changing the pharmacological effects of API.Owing to the promising potential to improve the solubility and bioavailability of poorly water-soluble API and lower cost and risk compared to developing a new compound,cocrystal and CAP systems are attracting increasing attention in the pharmaceutical field.Azelnidipine?AZE?and dipfluzine?DF?are dihydropyridines and piperazine calcium antagonists,respectively,which are outstanding in treating hypertension and reducing the incidence of adverse reactions such as headaches,dizziness and palpitations.However,AZE and DF are poorly water-soluble API,which induce low bioavailability.It is significant to screen the new solid complexes to improve the solubility and bioavailability of AZE and DF.Objective:1.To prepare different amorphous phase?AP?using AZE polymorphs,?and?-form,and screen CAP with CAF;To investigate the differences on physiochemical properties,thermodynamics stability involving transforming to crystalline AZE,and decomposition kinetics of prepared single AZE APs and screened CAP of AZE-CAF.2.To screen different solid complexes based on DF to improve the physicochemical properties such as solubility and dissolution rate in vitro.Furthermore,to evaluate differences on pharmacokinetics of DF and the screened different complexes in rats using HPLC method.Methods:1.The amorphous form?-AP and?-AP based on AZE polymorphs?-AZE and?-AZE were prepared by melting and quenching method.?-AZE-piperazine?AZE-PEZ?CAP was achieved using EtOH-assisted grinding method in?-AZE/PEZ 1:2 ratio,and characterizated by powder X-ray diffraction?PXRD?,temperature-modulated DSC?TMDSC?and fourier transform infrared spectroscopy?FT-IR?techniques.Based on the thermodynamic and kinetics formulas,thermodynamic stability and thermal decomposition kinetics analysis were performed using DSC and solubility method.2.Different solid complexes of DF were screened by using solvent-assisted grinding method;the screened DF-based complexes were characterized by PXRD,Differential scanning calorimetry?DSC?,TMDSC,FT-IR and single crystal X-ray diffraction?SCXRD?.Solubility of DF and its complexes in different media were determined by shake flask method.The dissolution rates of DF and its complexes in pH4.5 sodium acetate buffer solution were performed by the paddle method.The concentration of DF was determined by UPLC method.3.In vivo pharmacokinetics of DF and its complexes in rats were evaluated through determining of DF concentration by HPLC method.Results:1.A single T_g appeared above the room temperature for?-AP,?-AP and?-AZE-PEZ CAP,which indicated the stability under accelerated experimental condition.Comparing the FT-IT spectra of?-AP with that of?-Cry,the peak assigned to N-H vibration was broadened and shifted drastically;the double peaks assigning to C=O merged into a single peak.Similarly,comparing the FT-IT spectra of?-AP and CAP with that of?-Cry,the peak assigned to N-H vibration in amorphous phase was also broadened and shifted;and the double peak assigning to C=O merged into a single peak.The order of the solubility in 0.01 mol·L^-1 HCl at different temperatures is:?-AP>CAP>?-Cry>?-Cry>?-AP.At room temperature,the conversion reaction of?-AP?or CAP?to?-Cry occurred spontaneously,while,the conversion of?-AP to?-Cry was non-spontaneous.The thermodynamic stability of?-AP was higher than those of?-AP and CAP.2.Based on PXRD,DSC,TM-DSC,FT-IR,SCXRD analysis,five crystalline complexes and three CAPs were screened.Among five crystalline complexes,the complexes of DF-maleic acid,DF-fumaric acid,DF-malic acid and DF-propanedioic acid were in salt nature;Df-4-Hydroxybenzoic acid was salt cocrystal.The complexes of DF-tartaric acid,DF-saccharin and DF-salicylic acid were amorphous salt,CAP supramolecule involving hydrogen bonds and complexing amorphous phase involving ionic and hydrogen bonds,respectively.The equilibrium solubilities of the as-prepared complexes were significantly higher than that of DF;except for DF-saccharin and DF-salicylic acid,the dissolution rates of the complexes were significantly higher than that of DF?P<0.05?.3.The C_maxs of DF,DF-Fumaric acid,DF-4-Hydroxybenzoic acid,DF-Saccharin and DF-Salicylic acid were 0.26,0.55,0.50,0.35 and 0.42?g·mL^-1,respectively.The AUC_0-ts of DF,DF-Fumaric acid,DF-4-Hydroxybenzoic acid,DF-Saccharin and DF-Salicylic acid were 3.33,3.55,4.34,4.01 and 4.33?g·h·mL^-1,respectively.Compared with DF,the pharmacokinetics parameters C_max and AUC_0-t of DF-based complexes were improved?P<0.05?.The general trend was that the solid form of“salt”tended to cause higher C_max.Conclusions:1.The stability study on amorphous form?-AP,?-AP and CAP indicated that APs from different crystalline forms showed different physicochemical properties,such as solubility,dissolution rate and thermodynamic stability.When CAP was produced by connecting API with CAF through hydrogen bond,it improved thermodynamic stability compared with single API AP.it indicated that the hydrogen bonding between API and CAF was beneficial to stabilize the amorphous phase.2.DF is the suitable model API for screening complexes of different forms.Various forms of complexes based on DF,such as CAP,cocrystal and salt cocrystal,were screened in present study.Those screened complexes improved the bioavailability of DF.More importantly,it inferred that completely ionized salts tended to give rise to a higher C_max.This study pays more attention on screening various forms of solid complexes based on the same API and evaluating its physicochemical properties in vitro and bioavailability in vivo,which provide theoretical basis for developing different solid forms of an API based on different goals.